The majority of patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced disease confined to the chest yet technically unresectable. These patients have a poor prognosis with a median survival of about one year. In patients treated with surgery and pre-operative chemo-radiation, median survival improves to 15-17 months and pathologic complete response rates of 13-15% are observed. In an effort to improve on these results and minimize toxicity, molecularly targeted therapies are under development. In NSCLC, mutations and/or amplifications in Ras, EGFR (also known as Her-1 or erb-B1) and Her-2 (also know as erb-B2/neu or p185neu) frequently result in the activation of the PI3K-Akt pathway. Previous studies in NSCLC have found the frequency of Akt activation to range between 67-83%. Strategies which target the PI3K-Akt pathway sensitize human tumor cells to radiation in preclinical studies. However, there is currently no clinically effective inhibitor of the PI3K-Akt pathway. We have found that one class of drugs in common use clinically, the HIV protease inhibitors (HPIs) interfere with PI3K-Akt signaling. HPIs have been used continuously in patients with well characterized pharmacokinetics. We propose to examine the use of the HPI nelfinavir in non-HIV infected patients with NSCLC. The broad goals of this application are to explore the mechanisms by which nelfinavir results in sensitization and the development of the clinical use of nelfinavir as a radiation sensitizer. Specific Aim 1. To conduct a phase I trial of NFV in combination with radiotherapy and chemotherapy in patients with locally advanced NSCLC who are considered candidates for pre-operative treatment. Specific Aim 2. To determine the expression of signaling proteins that can be abnormally expressed in NSCLC resulting in activation of Akt, correlate with response to NFV and ultimately the outcome of patients. Specific Aim 3. To investigate in vitro the molecular mechanisms by which NFV results in sensitization. [unreadable] [unreadable] [unreadable]